Farach-Carson, Mary CLwigale, Peter Y2020-04-272020-11-012020-052020-04-24May 2020Sablatura, Lindsey Kay. "Complex 3D Culture Models for the Study of Bone Metastatic Prostate Cancer." (2020) Diss., Rice University. <a href="https://hdl.handle.net/1911/108397">https://hdl.handle.net/1911/108397</a>.https://hdl.handle.net/1911/108397EMBARGO NOTE: Submission was originally published under a 1 year embargo. The embargo has been extended until 2022-11-01.Prostate cancer (PCa) is the most prevalent form of cancer in men. Despite the enormous resource expenditures on research and development, few advances have been made that improve therapeutic outcomes for patients with relapsed or bone metastatic disease. The high attrition rate of potential anti-cancer drugs entering clinical trials indicates the need for a shift in our approach to modeling metastatic tumors in preclinical studies. As evidence mounts of the importance of microenvironmental cues in tumorigenesis, metastasis, treatment response, and recurrence, research has sought to bridge the gap between in vivo biological relevance and in vitro accessibility and throughput. Three-dimensional (3D) culture models allow experimental control over variables not easily manipulatable in vivo using mouse models, including the cell types and extracellular matrix cues present in the tumor microenvironment (TME). These high content models also support real time imaging of cancer cell behavior as they contact with other cells in the TME. Perfusable models can be used further, not only to add and remove nutrients and waste from cultured cells, but also to introduce perturbagens including anti-cancer drugs for testing personalized oncology. With this goal in mind, these studies tested the hypothesis that the use of complex 3D models containing cancer, stroma, and endothelial cells to reconstitute cellular interactions can replicate events that occur in the bone metastatic niche, allowing investigation into new methods of disrupting growth and progression of bone metastatic disease. Work described in chapters 2 and 3 developed a new high-content, perfusable, hydrogel-based system that permitted the tri-culture of diverse PCa patient-derived xenograft cells with microvascular endothelial cells and tumor stromal cells. The applications of this new pre-clinical model for drug screening and the study of cancer biology were demonstrated. Work in chapter 4 constructed a model of the bone marrow TME to examine endothelial cell promotion of PCa death/dormancy in the bone metastatic niche. Together, the work in these chapters establishes a new stepping stone for in vitro models of bone metastatic PCa, providing new tools for drug discovery and cancer research.application/pdfengCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.Prostate cancer3D modelsbone metastasesThesis2020-04-27